Preeclampsia is a hypertensive disorder that complicates up to 6-8% of pregnancies and remains the leading cause of maternal and perinatal morbidity and mortality (1, 2). Yet, despite extensive research efforts, the etiology of this multi-systematic disorder remains incompletely understood. Vascular endothelial activation followed by vasospasm appears to be the central feature in the pathogenesis of preeclampsia. Theories of its cause include abnormal implantation and development of the placenta, oxidative stress, impaired endothelial prostanoid and nitric oxide homeostasis, genetic polymorphisms, abnormal circulating autoantibodies and an abnormal maternal systematic inflammatory response (3, 4, 5, 6, 7). More recently, there has been increased focus on the effects of variations in the expression levels of modulators of angiogenesis, which cause symptoms of preeclampsia, including hypertension, proteinuria, endothelial cell activation and increased platelet aggregation (8, 9, 10, 11, 12).
Specifically, recent studies have reported that maternal serum concentrations of vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) are altered in patients with clinical preeclampsia (13, 14, 15). VEGF and PlGF are growth factors involved in placental development and both contribute to the mitogenic activity and angiogenesis that is crucial to a developing fetus. sFlt-1 is a splice variant of the Flt-1 receptor. It lacks the cytoplasmic and transmembrane domains of Flt-1, a receptor that binds to both VEGF and PlGF activating their signaling pathways. Increased serum sFlt-1 precedes the onset of clinically identifiable preeclampsia by approximately 5 weeks and reduced free PlGF is evident as early as the first trimester (13, 15, 16). In contrast, VEGF serum concentrations are low throughout pregnancy in women with clinical preeclampsia (15).
Such angiogenic factors also appear to be significant in the regulation of human kidney glomerular vascular physiology. Exogenous sFlt-1 administered to pregnant rodents leads to hypertension, proteinuria and glomerular endotheliosis (17). Similarly, neutralization of VEGF, a key mitogen survival factor for glomerular vascular endothelium, leads to increased apoptosis, impaired glomerular capillary repair and severe proteinuria (18). In severe preeclampsia, glomerular endotheliosis, a common characteristic of the disorder, further supports the link between the angiogenic factors altered in patients with hypertensive disorders and general kidney function (19, 20, 21, 22, 23).
Currently, there is no single test to predict or diagnose preeclampsia or to foretell the severity of the condition that will develop in a particular patient. Early symptoms include persistent headaches, blurred vision or sensitivity to light and abdominal pain. However, a diagnosis of preeclampsia is not typically made until increased blood pressure and protein in the urine (proteinuria) are revealed, typically in routine physician tests following the 20th week of pregnancy (1). Severe effects of preeclampsia, including seizures, cerebral hemorrhage, disseminated intravascular coagulation and renal failure, may appear very shortly following such diagnosis. These methods are imprecise and provide little insight into the likelihood of the most severe symptoms developing. Moreover, the current diagnostics require physician oversight and invasive methodologies, further delaying and complicating early and immediate assessment. An early and accurate method for the detection and diagnosis of preeclampsia and associated proteinuric hypertensive disorders is needed.